Aubrey de Grey wrote:
> Iuval Clejan wrote:
>> > Why is everyone insisting that there is a selection mechanism operating
> > prior to meiosis? Sorry Aubrey but I have not found support for this in
> > the references you provided (maybe I didn't understand).
>> The cellular selection that I and others (eg Nature 400:125, Nature 403:
> 500)
I think I had looked for one of these in the past but could not find it. I'll
let you know if one of these is wrong.
> have discussed occurs during ovulation. It is driven (in my model,
> at least) by prior, intracellular selection for any mutant mtDNA that a
> given oocyte may contain during the many years while it is quiescent
> and non-dividing -- similar to what happens in muscle. The thing that
> happens much earlier is a mtDNA population bottleneck; that process is
> not selection in and of itself, but it amplifies the power of the later
> selection process by reducing the possibility that there will be some
> but not many mutant mtDNA genomes in the oocyte at the time of ovulation.
I need to read those references because I don't understand this. Why is some
but not many bad? Many is worse than some. What is the net result of the
selection process? Very few mutants?
>>> > Maybe something similar occurs in replicating
> > oocytes to what occurs in replicating yeast with ERCs (what is the
> > biochemical reason for the asymmetry in that case?)
>> Still unclear, I believe. One hypothesis is that the extrusion of
> material into the daughter cell is a rather carefully regulated process
> such that things typically only get into the daughter cell by an active
> process, and ERC's are not actively taken there so they predominantly
> stay in the mother.
>> > 3. What proteins that are involved in mitochondrial welfare are coded
> > for by the nucleus? Anything for repair of mtDNA? Replication of mtDNA/
> > transcription of mtDNA?
>> All of the above. The only proteins that are encoded in the mtDNA are
> 11 subunits of the respiratory chain and two of the ATP synthase.
>> > Why is tellomerase anti-apopototic? Is it
> > possible that senescent cells stop expressing some of the genes
> > necessary for mitochondrial welfare?
>> The only theory I know of (see Zhang et al, Genes Dev. 13:2388) is that
> telomerase specifically inhibits apoptosis caused by aneuploidy.
But Fu et al, J. Bio. Chem. 274 11:7264 show that it inhibits apoptosis
caused by a few apoptotic inducers that have nothing to do with
aneuploidy.Conversely tellomerase inhibitors enhance apoptosis in the
presence of the apoptotic inducers. Also a correlation was observed between
decrease in tellomerase activity and sensistivity to apoptosis after
differentiation of cells into nerve cells, but I didn't see a causal link
there. I also didn't understand if they were using immortalized cells or not,
and if the latter how short their tellomeres were (I recall papers saying
that senescence is entered much before the chromosomes are short enough for
aneuploidy and that P53 somehow sensed the shortness of the tellomeres and
stopped the cell cycle)
> When
> telomerase is absent and telomeres get critically short, chromosomes
> get joined end-to-end (Robertsonian fusions) and aneuploidy results.
> However, the possibility remains very open that telomere shortening
> and consequent gene-expression changes could induce apoptosis in other
> ways too. Eugenia Wang and others found some time ago that fibroblasts
> become *less* apoptosis-prone when they approach replicative senescence,
> but others have disputed that finding and it's now known that other cell
> types show the reverse.
>> > I am thinking that one of the main
> > differences between mitos and aerobic bacteria is that mitos are
> > symbiotic with the nucleus, whereas bacteria are rugged individualists.
> > So what if mitos are mutating at a high rate, so are bacteria, as long
> > as they keep reproducing they will survive.
>> Ah, but that's because the mutant bacteria stop reproducing [so well].
> Since the mtDNA encodes none at all of the machinery for mitochondrial
> biogenesis, mutations aren't necessarily selected against.
I think you hypothesized (I saw one of your abstracts on medline) that some
mutations are actually selected FOR, although by a different mechanism having
to do with less likely lysosomal degradation of the mito which doesn't
produce as much ROS.
>>> > One thing that might keep
> > them from reproducing is a nuclear clock (e.g. tellomere shortening
> > followed by activation of P53 followed by apoptotic signals) This
> > scenario would favor mitos in post mitotic cells, if other mechanisms
> > didn't come into play.
>> You've lost me here. Favour mutant mitos in post mitotic cells?
Mutant or not, as long as they're in cells that don't have shortening
tellomeres (post mitotic cells) they'll be able to either replicate, repair
or transcribe their own DNA better than the ones in post mitotic cells, which
get a signal from the nucleus that stops the aforementioned functions. Please
try to poke holes in this hypothesis. If no conceptual holes, I think there
are a few experiments that can be done to test it.
-Iuval